We recently introduced the concept of toll-like receptor (TLR)-mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. We first prepared and characterized unnatural (+)-naloxone in 1978 as an opioid receptor inert research tool useful for detecting opioid receptor mediated effects when used in conjunction with (-)-naloxone, a high affinity clinical useful narcotic antagonist. We have now shown that (+)-naloxone and (+)-naltrexone, long thought to be inert compounds, are functional antagonists of TLR-4 receptors and that selective acute functional antagonism of TLR4 by (+)-naloxone results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (-)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use. Coadministration of (+)-naloxone or (+)-naltrexone would not interfere with the desired actions of morphine and similar agonists since the (+)-isomers are inert to opioid receptors as mentioned above. We are continuing to synthesize unnatural opioids and antagonists and study their effects on TLR receptors. Morphine-3-glucoronide (M3G) is a major morphine metabolite detected in cerebrospinal fluid of humans receiving systemic morphine that induces pain independent of classic opiate receptors via unknown mechanisms. We showed earlier that morphine activates toll-4 receptors (TLR-4) and that this activation opposes morphine analgesia mediated via classic opioid receptors. We have now found that M3G also activates TLR-4 receptors and that this activation is blocked by the TLR-4 antagonist (+)-naloxone. This effect is independent of classic opioid receptors since (+)-naloxone is inert to these receptors. Intrathecal M3G induced potent allodynia and hyperalgesia in vivo that was blocked or reversed by interleukin-1 (IL1) receptor antagonist, minocycline and TLR-4 antagonist (+)-naloxone. These and other data implicate TLR4 and IL1 mediated components to M3G-induced effects.